Corso Jasmin, Pan Kuan-Ting, Walter Roland, Doebele Carmen, Mohr Sebastian, Bohnenberger Hanibal, Ströbel Philipp, Lenz Christof, Slabicki Mikolaj, Hüllein Jennifer, Comoglio Federico, Rieger Michael A, Zenz Thorsten, Wienands Jürgen, Engelke Michael, Serve Hubert, Urlaub Henning, Oellerich Thomas
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany;
Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany;
Proc Natl Acad Sci U S A. 2016 May 17;113(20):5688-93. doi: 10.1073/pnas.1601053113. Epub 2016 May 6.
Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.
伯基特淋巴瘤（BL）是一种高增殖性B细胞肿瘤，采用强化化疗进行治疗，但由于其毒性，通常不适用于老年人或发展中国家的地方性BL患者。BL细胞的存活依赖于B细胞抗原受体（BCR）转导的信号。然而，持续性以及活化的BCR信号网络及其在BL靶向治疗中的相关性仍不清楚。我们通过定量磷酸化蛋白质组学系统地表征和比较了BL中持续性和活化的BCR信号，以鉴定新的BCR效应器和潜在的药物靶点。我们在BL细胞中鉴定并定量了约16,000个磷酸化位点。在这些位点中，909个与持续性BCR信号相关，而984个磷酸化位点在BCR激活后受到调节。大多数已鉴定的BCR信号效应器在B细胞或淋巴瘤的背景下尚未被描述。这些新鉴定的BCR效应器中的大多数预计参与激酶、转录和细胞骨架动力学的调节。尽管持续性和活化的BCR信号共享相当数量的效应蛋白，但我们在持续性BCR信号中鉴定出了不同的磷酸化事件。我们研究了一些新鉴定的BCR效应器的功能相关性，结果表明分别被描述为膜运输和细胞骨架相关过程调节因子的ACTN4和ARFGEF2对BL细胞存活至关重要。因此，本研究为持续性和活化的BCR信号提供了一个全面的数据集，并鉴定了可能与BL细胞存活相关的效应蛋白，从而可能有助于开发新的BL治疗方法。
